Volume 9, Issue 5 pp. 698-708

HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

S. Michal Jazwinski

S. Michal Jazwinski

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

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Sangkyu Kim

Sangkyu Kim

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

Contributed equally.

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Jianliang Dai

Jianliang Dai

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

Genetics Department, University of Georgia, Athens, GA 30602, USA

Contributed equally.

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Li Li

Li Li

Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

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Xiuhua Bi

Xiuhua Bi

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

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James C. Jiang

James C. Jiang

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

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Jonathan Arnold

Jonathan Arnold

Genetics Department, University of Georgia, Athens, GA 30602, USA

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Mark A. Batzer

Mark A. Batzer

Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA

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Jerilyn A. Walker

Jerilyn A. Walker

Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA

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David A. Welsh

David A. Welsh

Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

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Christina M. Lefante

Christina M. Lefante

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

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Julia Volaufova

Julia Volaufova

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

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Leann Myers

Leann Myers

Department of Biostatistics, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

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L. Joseph Su

L. Joseph Su

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

Present address: Modifiable Risk Factors Branch, National Cancer Institute, Rockville, MD 20892, USA.

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Dorothy B. Hausman

Dorothy B. Hausman

Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA

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Michael V. Miceli

Michael V. Miceli

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

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Eric Ravussin

Eric Ravussin

Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA

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Leonard W. Poon

Leonard W. Poon

Institute of Gerontology, University of Georgia, Athens, GA 30602, USA

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Katie E. Cherry

Katie E. Cherry

Department of Psychology, Louisiana State University, Baton Rouge, LA 70803, USA

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Michael A. Welsch

Michael A. Welsch

Department of Kinesiology, Louisiana State University, Baton Rouge, LA 70803, USA

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for the Georgia Centenarian Study and the Louisiana Healthy Aging Study

for the Georgia Centenarian Study and the Louisiana Healthy Aging Study

Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA

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First published: 16 September 2010
Citations: 58
S. Michal Jazwinski, PhD, Department of Medicine, Tulane University Health Sciences Center, 1430 Tulane Ave., SL-12, New Orleans, LA 70112, USA. Tel.: 504 988 8253; fax: 504 988 8835; e-mail: [email protected]

Summary

The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity.

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